KR20080071170A - Stabilized lanthanum carbonate compositions - Google Patents

Abstract

Stabilized lanthanum carbonate compositions containing a monosaccharide or disaccharide stabilizing agent are disclosed. Subjects having hyperphosphatemia can be treated by administering a pharmaceutical composition containing a therapeutically effective amount of the stabilized lanthanum carbonate formulation.

Description

STABILIZED LANTHANUM CARBONATE COMPOSITIONS

This application claims as a priority US patent application Ser. No. 11 / 272,569, filed November 9, 2005, which is incorporated herein by reference.

The present application relates to a method for treating a subject with hyperphosphatemia by administering a stabilized lanthanum carbonate composition comprising a monosaccharide or disaccharide stabilizer and a pharmaceutical composition containing a therapeutically effective amount of the stabilized lanthanum carbonate composition. will be.

Hyperphosphatemia is a prominent problem in patients with chronic renal failure or chronic kidney disease (CKD). Approximately 70% of patients with end stage renal disease (ESRD) undergoing renal dialysis need treatment for hyperphosphatemia. This disease can lead to severe bone problems and metastatic calcification of the skin and major organs, and is associated with high morbidity and mortality. Traditional dialysis does not reduce blood phosphate levels, so they rise in time. Elevated phosphate levels are controlled using a combination of dietary restrictions and phosphate-binding agents.

Another problem in patients with chronic renal failure is secondary hyperparatyroidism. Avoiding and treating secondary parathyroidism is an important issue for patients with chronic renal failure.

Certain specific forms of lanthanum carbonate have been used to treat hyperphosphatemia in patients with kidney disease (see for example JP 1876384).

U.S. Pat.No. 5,968,976 of the same applicant as the applicant of the present invention discloses the preparation of certain hydrates of lanthanum carbonate and the use in pharmaceutical compositions for treating hyperphosphatemia.

However, lanthanum carbonate tends to decompose into lanthanum hydroxycarbonate. This process is accelerated by moisture and heat. There is a need in the art to prevent such degradation, because current regulatory regulations prohibit detectable decarboxylation in administration to patients. The present invention is based on the unexpected finding that monosaccharides or disaccharides significantly slow down the degradation of lanthanum carbonate, while more complex sugars (eg cornstarch and β-cyclodextrin) are not. Stabilized compositions of lanthanum carbonate can be used in pharmaceutical compositions and can be used to treat subjects with hyperphosphatemia.

Summary of the Invention

According to the invention, a pharmaceutically effective amount of lanthanum carbonate having the formula La ₂ (CO ₃ ) ₃ .xH ₂ O, wherein x is a number from 0 to 10, and at least one pharmaceutically acceptable monosaccharide or disaccharide is provided a stabilized lanthanum carbonate composition comprising a (where a monosaccharide or disaccharide is, relative to the total weight of the composition, at least present in an amount of about 1%). As will be described below, the present invention is a subject vulnerable to or suffering from hyperphosphatemia, a chronic kidney disease (CKD) risk subject suffering from stage 1 to 5 CKD, a subject vulnerable to or suffering from soft tissue calcification associated with CKD, secondary It can be used to treat a subject vulnerable to or suffering from hyperparathyroidism, or a subject vulnerable to or suffering from other symptoms not yet known that require phosphate uptake control. The invention may also be used in the treatment of subjects described in US Patent Application No. 11 / 272,563, entitled "Treatment of Chronic Kindey Disease (CKD) Subjects using Lanthanum Compounds," filed on the same date as this application.

Chew tablet form of lanthanum carbonate eating (available from ^{shire Pharmaceuticals, Wayne, PA Fosrenol ®} ) has been approved by the US Food and Drug Administration to treat hyperphosphatemia of ESRD subjects, it is currently commercially available.

The above technical and other features and advantages of the present invention will be better understood with reference to the following detailed description of the invention.

1 is an XRPD (x-ray powder diffraction) pattern of substantially pure hydrated lanthanum carbonate having a water content equivalent to approximately 4-5 moles of water.

FIG. 2 illustrates the XRPD pattern of substantially pure cornstarch, β-cyclodextrin, dexrate, D-sorbitol, D-mannitol and lanthanum anhydrous carbonate.

3 illustrates the XRPD pattern of lanthanum carbonate hydrated at 60 ° C./95% RH (relative humidity) for 0, 1, 2, 3, 4, and 7 days.

4 illustrates the XRPD pattern of lanthanum carbonate hydrated at 60 ° C./65% RH for 0, 1, 2, 3, 4, 7, 14 and 21 days.

FIG. 5 illustrates the XRPD pattern of a 1: 1 (weight) mixture of lanthanum carbonate / D-mannitol hydrated at 60 ° C./65% RH for 0, 1, 2, 3, 4, 7, and 14 days.

6 illustrates the XRPD pattern of a 1: 1 (weight) mixture of lanthanum carbonate / D-sorbitol hydrated at 60 ° C./65% RH for 0, 1, 2, 3, 4, 7, 14, and 21 days. .

FIG. 7 illustrates an XRPD pattern of a 1: 1 (weight) mixture of lanthanum carbonate / dextrin hydrated at 60 ° C./65% RH for 0, 1, 2, 3, 4, 7, 14, and 21 days.

FIG. 8 illustrates the XRPD pattern of a 1: 1 (weight) mixture of lanthanum carbonate / β-cyclodextrin hydrated at 60 ° C./95% RH for 0, 1, 2, 3, 4, 7, and 14 days.

FIG. 9 illustrates the XRPD pattern of a 1: 1 (weight) mixture of lanthanum carbonate / corn starch hydrated at 60 ° C./95% RH for 0, 1, 2, 3, 4, 7, and 14 days.

FIG. 10 illustrates the XRPD pattern of a 1: 1 (weight) mixture of anhydrous lanthanum carbonate / D-mannitol at 60 ° C./95% RH for 0, 1, 2, 3, 4, and 7 days.

FIG. 11 illustrates the XRPD pattern of a 1: 1 (weight) mixture of lanthanum carbonate / anhydrous lactose hydrated at 60 ° C./95% RH for 0, 1, 2, 3, 4, 7, and 14 days. .

FIG. 12 illustrates the XRPD pattern of a 1: 1 (weight) mixture of lanthanum carbonate / lactose monohydrate hydrated at 60 ° C./95% RH for 0, 1, 2, 3, 4, 7, and 14 days.

FIG. 13 illustrates the XRPD pattern of a 1: 1 (weight) mixture of lanthanum carbonate / microcrystalline cellulose hydrated at 60 ° C./95% RH for 0, 1, 2, 3, 4, 7, and 14 days.

FIG. 14 illustrates the XRPD pattern of a 96: 4 (weight) mixture of lanthanum carbonate / D-mannitol hydrated at 60 ° C./95% RH for 0, 1, 2, 3, 4, 7, and 14 days.

FIG. 15 shows 25 ° C./60% RH, 30 ° C./60% RH, and 40 ° C./75 in unformulated hydrated lanthanum carbonate and formulated hydrated lanthanum carbonate containing approximately 50% (weight) dexrate. Degradation to lanthanum hydroxycarbonate occurs up to 24 months in% RH.

1. General Definition

As used herein, the term “treat”, “treating”, or “treatment” refers to hyperphosphatemia, chronic kidney disease (CKD), severe bone problems, soft tissue calcification, secondary parathyroidism, or other yet unknown Prevention, reduction, alleviation, partial or complete relief of symptoms requiring control of phosphate absorption.

Also, as used herein, “subject” refers to a mammal (eg, any veterinary patient, such as a domestic animal such as a dog or cat), or a human patient.

The term “about” or “approximately” refers to within an acceptable range for a particular parameter specified when determined by one of ordinary skill in the art, which depends in part on how the numerical value is measured or determined, eg, what are the limits of the measurement system. Depends. For example, "about" can mean a range of up to 20% of a predetermined value. Otherwise, particularly with respect to biological systems or processes, the term may mean within the range of orders of magnitude, preferably 5 times, more preferably 2 times that value.

As used herein, the term “dextrate” is mostly dextrose (eg, at least about 93.0%, up to about 99.0%, calculated on the basis of drying), and hydrolysis of starch by a controlled enzyme Refers to a purified mixture of sugars derived from The dexrate may be in anhydride or hydrate form. "Dextrate" refers to a dextrate as defined in the memorandum found in National Formulary 21 (Webcom Limited in Toronto, Canada; 2003). Dextrate is under the trade name Emdex ^® and is commercially available from JRS Pharma (Patterson, NY).

As used herein, "stabilized composition" or "stabilized lanthanum carbonate composition" refers to a composition containing lanthanum carbonate (in any hydrated state, including lanthanum anhydride) and one or more monosaccharides or disaccharides. Preferably, the total amount of monosaccharides, disaccharides, or combinations thereof is present in the composition in an amount of at least about 1 wt%. Lanthanum carbonate in the stabilized lanthanum carbonate composition decomposes into lanthanum hydroxycarbonate alone or at a slower rate than lanthanum carbonate in the absence of other materials. For example, after 7 days at 95% relative humidity at 60 ° C., lanthanum carbonate in the lanthanum carbonate composition stabilized with at least about 4% monosaccharides, disaccharides or combinations thereof is detectable to the extent of lanthanum (by existing analytical techniques). It does not decompose into hydroxycarbonate. In contrast, under the same conditions, substantially pure lanthanum carbonate starts to decompose into lanthanum hydroxycarbonate after only one day.

As used herein, a “pharmaceutically effective amount” or “therapeutically effective amount” means (i) reducing the subject's plasma phosphate levels to a detectable degree, or (ii) maintaining the subject's plasma phosphate levels at a minimum, substantially constant level. Refers to the amount or dosage of sufficient lanthanum carbonate to achieve.

As used herein, "lanthanum carbonate" is a term that encompasses all hydrated forms of lanthanum carbonate, as well as anhydrous lanthanum carbonate.

As used herein, "percent" or "%" refers to an estimate based on the weight of the total composition.

The term “substantially pure lanthanum carbonate” refers to lanthanum carbonate having a purity of at least about 90% based on anhydride.

The term "symptom" in hyperphosphatemia, CKD, soft tissue calcification associated with CKD, or secondary hyperthyroidism risk subjects or subjects with the disease may be any functional or structural abnormality experienced by the subject and may be renal function. It may refer to a child dysfunction, for example, to those described in section 6. Among other functional abnormalities, for example, one or more of the following signs may indicate a risk for CKD or the presence of CKD: creatine concentration of about 1.6 mg / dL or higher, blood urea nitrogen (BUN) of about 20 mg / dL or higher ), Blood phosphate levels of at least about 4.5 mg / dL, any detectable amount of urine blood, at least about 100 mg / dL urine protein, at least about 100 mg / dL urine albumin concentration, at least about 150 pg / mL blood source ( intact) parathyroid hormone (PTH) concentration, or glomerular filtration rate (GFR) of about 90 mL / min / 1.73 m 2 or less.

2. Lanthanum Carbonate

The stabilized composition of the present invention may contain lanthanum carbonate having the formula La ₂ (CO ₃ ) ₃ .xH ₂ O, wherein x is a number from 0 to 10. Preferably, x is a number from 3 to 8, more preferably a number from 3 to 6. Most preferably, x can be an average value between about 4 and 5. The hydration level of the lanthanum compound can be measured by methods known in the art, for example thermo gravimetric analysis (TGA) or x-ray powder diffraction (XRPD).

Lanthanum carbonate has a tendency to decompose into lanthanum hydroxycarbonate through decarboxylation, as follows:

La ₂ (CO ₃ ) ₃ + H ₂ O ----> 2LaOHCO ₃ + CO ₂

The hydroxycarbonate product is derived from electrophilic or nucleophilic attack on the carbonyl moiety of lanthanum carbonate. This process is overspeeded by the presence of moisture or heat and appears to be self-catalytic. Therefore, even if the amount of lanthanum hydroxy carbonate in the lanthanum carbonate formulation is very small, a rapid and excessive decomposition reaction is caused. Thus, there is a need in the art to prevent such degradation reactions, as pointed out above, current regulatory regulations prohibit detectable decarboxylation in administration to patients. As a result, formulations which eliminate or substantially slow the degradation reaction are very desirable.

According to the present invention, the presence of at least about 1% of one or more monosaccharides or disaccharides in the lanthanum carbonate composition significantly slows down the degradation of the lanthanum carbonate. Surprisingly, the addition of such stabilizers is effective in minimizing the rate of degradation regardless of the degree of hydration of lanthanum carbonate (if present). For example, unformulated lanthanum carbonate decomposes to lanthanum hydroxycarbonate within about 9 to 12 months at room temperature, while detected in the presence of monosaccharides or disaccharides (about 70 wt%) for at least 3 years under standard atmospheric conditions. Possible decomposition does not occur.

While not intending to be bound by any theory, the stabilizing effects of the monosaccharide and disaccharide stabilizers of the present invention are believed to be due to the availability of the -OH group, which is a reactive alcohol on such materials, while polysaccharides (where the alcohol groups are further Reacts and binds to monosaccharide units). Water reacts favorably with the available alcohol groups on monosaccharides or disaccharides, but the carbonyl groups of lanthanum carbonate are left intact to prevent degradation of anti-hyperphosphatemic agents.

The degradation of lanthanum carbonate to lanthanum hydroxycarbonate can be observed by examining the x-ray powder diffraction (XRPD) pattern of the lanthanum carbonate sample that may have been degraded. The presence of an observable peak corresponding to lanthanum hydroxycarbonate in the sample pattern indicates that it is being degraded, while the absence of an observable peak indicates no detectable degradation. Example 5 showed the use of the XRPD pattern to observe degradation from lanthanum carbonate to lanthanum hydroxycarbonate.

Further advantages of the present invention include, but are not limited to, reduced storage and handling costs due to the elimination of the requirement to refrigerate the stabilized lanthanum carbonate formulation. Stabilized formulations also provide longer product life, resulting in less waste due to inventory.

Other advantages of the formulations described herein can be found in the parent application of this application (US Patent Application No. 10 / 926,330), wherein the formulation of lanthanum carbonate with monosaccharides or disaccharides increases the aesthetics of the formulation without liquid. It allows the formulation to be administered in chewable form.

3. Monosaccharides and Disaccharides Stabilizer

The stabilized composition of the present invention contains at least one monosaccharide or disaccharide. Monosaccharides, disaccharides or mixtures thereof are present in a total amount of at least about 1%, preferably about 4 to about 90%, more preferably about 30% to about 70% by weight of the composition.

Monosaccharides suitable for use as stabilizers in the formulations of the invention include glyceraldehyde, erythrose, threose, ribose, lyxose, xylose. , Arabinose, allose, talsoe, gulose, mannose, glucose (e.g. in the form of corn syrup), idose, Galactose, altrose, dihydroxyacetone, erythrulose, ribulose, xyloketose, psycose, tagatose Sorbose, fructose, sorbitol, sorbitol, xylitol, inositol, erythritol, and mannitol in the D- or L- form and its derivatives And analogs, including but not limited to. Monosaccharides suitable for use in the present invention may be in cyclic (α- or β-form) or acyclic form and may be used as mixtures in the present invention. Other suitable monosaccharides include (D- glucose such as Cerelose ^® which is commercially available from e. G. Fisher Scientific (Hampton, NH)) dextrose.

Suitable disaccharides for use as stabilizers in the present invention include sucrose (sucrose) (e.g., Domino Foods in Baltimore, Sugartab ^®, available from Di-Pac ^® type, JRS Pharma (Patterson, NY), available from MD, Confectionery sugar, or Nutab, lactose (including anhydrous lactose and lactose monohydrate), maltose, isomaltose, cellobiose, trehalose, maltitol (malquetol) Lycasin ^® type, available from Lestrem, France)), iso malteu (isomalt), lactitol (lactitol), including, mixtures thereof, derivatives and analogs, are not limited. Disaccharides of the invention also include any combination of two monosaccharides linked by glycosidic bonds. The disaccharide can be a monodisaccharide (ie, composed of the same two monosaccharides), or a heterodisaccharide (ie, composed of two different monosaccharides). In addition, monosaccharides and disaccharides can be used in the same formulation.

Other suitable monosaccharides and disaccharides can be found in the following literature: Remington: The Science and Practice of Pharmacy (20th Edition, AR Gennaro editor, Lippincott Baltimore, MD: Williams and Wilkins, 2000) pages 409-413; And ^{Biochemistry (2 nd Edition, Voet and} Voet, New York: John Wiley & Sons, Inc., 1995) pages 251-276. Hydrolyzed starches containing monosaccharides and / or disaccharides may also be used in the formulations of the present invention.

As monosaccharides or disaccharide stabilizers, dexrate or sorbitol may preferably be used, the amount being about 4 to about 90 wt% of the weight of the formulation. In a preferred embodiment of the formulation of the invention, the dexrate as a stabilizer is included in an amount of about 70 wt% of the formulation. In another preferred embodiment of the invention, sorbitol as a stabilizer is included in an amount of about 30 wt% of the weight of the formulation.

4. Additives ( excipient )

The stabilized formulation of the present invention may further comprise at least one additive. The additives used in the formulations to be administered by the present invention should be suitable for oral administration to a subject lacking renal function. Additives may include diluents, binders, and lubricants / glidants. Agents such as other disintegrants, pigments and flavoring / sweetening agents may also be added to the formulation.

Suitable diluents are commercially available, for example, from calcium sulfate dihydrate, oligosaccharides, isomaltoligosaccharides, erythritol, polydextrose, dextrin, starch, maltodextrin, calcium lactate trihydrate, microcrystalline cellulose (such as GFS Chemicals (Powell, OH)). Being Avicel ^® ), hydrolyzed cereal solids (such as Maltrons or Mor-Rex ^™ ), amylose, or glycine. Additional diluents can include monosaccharides and disaccharide stabilizers as described above. One or more diluents may be present in the formulation. The total diluent amount may be about 1 to about 90 wt%, preferably about 4 to about 90 wt%, most preferably about 40% to about 80 wt%, based on the weight of the composition.

Suitable lubricants are, for example, magnesium stearate, talc, polyethylene glycol, silica, colloidal anhydrous silica, colloidal silicon dioxide, hydrogenated vegetable oil, glyceryl behenate or glyceryl monostearate Can be selected from. One or more lubricants may be present in the formulation. The total lubricant amount can be from about 0.1 to about 6.0 wt%, preferably from about 0.1% to about 5.0 wt%, most preferably from about 0.1 to about 4.0 wt%, based on the weight of the composition.

Useful glidants can be selected, for example, from silica, colloidal anhydrous silica, colloidal silicon dioxide, or talc. One or more glidants may be present in the formulation. The total glidant amount may be about 0.1 to about 6.0 wt%, preferably about 0.1 to about 5.0 wt%, most preferably about 0.1 to about 4.0 wt%, based on the weight of the composition.

It may be advantageous to incorporate antioxidants such as ascorbic acid, alpha tocopherol or butylated hydroxyanisole in the formulation to increase shelf life. One or more antioxidants may be present in the formulation. The total antioxidant amount can be about 0.0001 to 1.0 wt%, preferably about 0.001 to about 0.1 wt%, most preferably 0.005 to 0.05 wt%, based on the weight of the composition.

5. Additional Active Ingredients

5.1. lanthanum Carbonate  And vitamin D containing Formulation

Occasionally, subjects suffering from symptoms of hyperphosphatemia or CKD may also be vitamin D deficient. The level of 25-hydroxy vitamin D ₂ is as low as about 16 ng / mL or less, and the goal of treatment is to raise it to about 16 ng / mL or more. The level of 1,25-dihydroxy vitamin D2 is as low as about 22 pg / mL, and the goal is to raise it to levels above about 22 pg / mL. Therefore, it may be desirable to prepare a formulation containing lanthanum carbonate and vitamin D or analogs of vitamin D and administer it to a patient.

 Examples of vitamin D sources that may be used in the formulations of the present invention include 1,25 dihydroxy-vitamin D, active metabolites of vitamin D (calcitriol, rocalcitrol). . Examples of suitable vitamin D analogs include doxercalciferol (available from Hectorol®, Bone Care International, Middleton, WI), paricalcitol (Zemplar®, Abbott Laboratories, Abbott Park, IL) Available). One or more vitamin D sources or vitamin D analogs may be present in the formulation.

Vitamin D may be administered in separate dosage forms, but may also be administered in conjunction with the dosage forms of the invention. In a specific example, a patient in need of treatment is administered vitamin D 100 USP once a day and 250 mg of a stabilized lanthanum carbonate formulation three times a day.

5.2. lanthanum Carbonate  And calcium sources Formulation

Subjects with hyperphosphatemia or those with signs of CKD often suffer from hypocalcaemia (ie, blood calcium levels below about 8.5 mg / dL). Therefore, formulations of the present invention may include lanthanum carbonate and calcium sources.

Examples of forms of calcium include calcium carbonate (eg, available from Tums ^® , GlaxoSmithKline, Uxbridge, UK), calcium acetate (eg, available from PhosLo ^® , Nabi Biopharmaceuticals, Boca Raton, FL), and CaCl ₂ is included. One or more calcium sources may be present in the formulation.

The calcium source may be administered in separate dosage forms, but may be administered simultaneously with the dosage forms of the present invention. In specific embodiments, patients in need of treatment may be administered 1-2 tablets containing 200 mg as calcium and 250 mg of stabilized lanthanum carbonate formulation three times a day.

5.3. Complex containing lanthanum and vitamin K Formulation

Subjects suffering from hyperphosphatemia or signs of CKD may be vitamin K deficiency. In another embodiment of the invention, a formulation of the invention in combination with vitamin K is administered to a subject suffering from signs of hyperphosphatemia or CKD to alleviate vitamin K deficiency.

Examples of vitamin K sources include vitamin k1 (phlloquinone), vitamin K2 (menaquinone), and vitamin K3 (menadione).

Vitamin K may be formulated in the same formulation as the lanthanum formulation, or may be provided in different formulations. In a specific embodiment, 2.5-25 mg of vitamin K1 is administered once a day to a subject in need thereof, and the lanthanum formulation is administered three times a day.

6. Stabilized Lanthanum Carbonate As a formulation  Subject to be treated

Subjects vulnerable to or suffering from hyperphosphatemia, subjects with chronic kidney disease (CKD) risk with CKD levels of 1 to 5, subjects vulnerable to or suffering from soft tissue calcification associated with CKD, vulnerable to or suffering from secondary hyperthyroidism Subjects, or subjects who are susceptible to or suffering from unexplained symptoms requiring phosphate uptake control, can be treated by administering a therapeutically effective amount of the stabilized lanthanum carbonate formulation of the present invention.

6.1. Chronic kidney disease ( CKD )

The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (herein referred to as "NKF-K / DOQI" or "K / DOQI") refers to chronic kidney disease (CKD). 1) have a kidney injury defined as structural or functional abnormality of the kidney for at least 3 months with or without a decrease in glomerular filtration rate (GFR), or (2) at least 3 months with or without kidney damage Is defined as having a GFR of less than 60 mL / min / 1.73 m ² . Structural or functional abnormalities are graded by signs such as abnormalities found in imaging studies and indicators of pathological abnormalities or kidney damage, including the composition of blood or urine.

Examples of kidney injury indicators include plasma creatine concentrations of at least about 1.6 mg / dL and blood urea nitrogen (BUN) concentrations of at least about 20 mg / dL. Typically, both of these indicators are elevated in individuals with CKD. Additional indicators of kidney damage include hematuria (ie, a detectable amount of blood in the urine), proteinuria (ie, protein concentration in urine above about 100 mg / dL), albuminuria (ie, in urine above about 100 mg / dL) Albumin concentration), blood primary parathyroid hormone (PTH) concentration of at least about 150 pg / mL, or blood phosphate levels of at least about 4.5 mg / dL. One particular indicator of kidney disease is a GFR rate above normal (ie, a GFR above about 90 mL / min / 1.73 m ² ), but GFR below normal also indicates CKD.

K / DOQI published guidelines defining five different stages of CKD (Am J Kidney Dis. 2001, 37 (suppl 1): S1-S238). The following table describes each of the five stages of CKD and the GFR range of each stage.

step Explanation GFR (mL / min / 1.73m ² ) Danger 90-120 (with CKD symptoms) One Normal or Elevated GFR and Kidney Injury ≥90 2 Slightly reduced GFR and kidney damage 60-89 3 Moderately Reduced GFR 30-59 4 Greatly reduced GFR 15-29 5 Renal Dysfunction (ESRD) <15 (or dialysis)

Hyperphosphatemia in CKD subjects has several secondary symptoms. When the subject suffers from hyperphosphatemia, excessive plasma phosphate precipitates calcium in the plasma resulting in extra-skeletal calcification outside of a wide range of normal sites. Undesired deposition of calcium can occur in cardiovascular tissue, resulting in an increased risk of cardiovascular complications that can lead to death. In addition, increased plasma phosphate reduces calcium absorption in the intestine. Both mechanisms work simultaneously to reduce plasma calcium levels.

Decrease in plasma calcium levels can lead to increased production of parathyroid hormone (PTH) and the development of secondary secondary parathyroidism. In addition, recent studies show that high phosphate levels can directly stimulate PTH secretion, leading to secondary parathyroidism. Persistent stimulation of PTH secretion leads to cell hyperplasia of the parathyroid glands and may require parathyroid resection if necessary.

The method of the present invention, which involves the administration of a stabilized lanthanum carbonate formulation, lowers plasma phosphate levels, as well as stage 1 including hyperphosphatemia, out-of-site calcification of the bone, plasma hypocalcemia, and secondary hyperthyroidism. Is believed to mitigate the consequences of CKD in subjects who have or are vulnerable to five levels of CKD. However, it is to be understood that the invention is not limited to any particular biochemical or pathological mechanism.

6.2. Hyperphosphatemia  Treatment method

Subjects susceptible to or suffering from hyperphosphatemia can be treated by administering a therapeutically effective amount of the stabilized lanthanum carbonate formulation of the invention. Hyperphosphatemia herein refers to the symptoms of a patient having a blood phosphate level of about 4.5 mg / dL or more.

6.3. Chronic kidney disease ( CKD ) Treatment method

Subjects with signs of chronic kidney disease (CKD) can be treated by administering to the subject a therapeutically effective amount of the stabilized lanthanum carbonate formulation of the present invention. As also indicated above, the subject to be treated may be a CKD risk subject or may be a subject with CKD at any of stages 1 to 5 as defined above. CKD risk subjects or subjects with CKD at any of stages 1-5 may have one or more of the following signs: blood phosphate levels of at least about 4.5 mg / dL, plasma creatine concentration of at least about 1.6 mg / dL , BUN greater than about 20 mg / dL, detectable amount of blood in urine, protein concentration in urine greater than about 100 mg / dL, albumin concentration in urine greater than about 100 mg / dL, blood source greater than about 150 pg / mL Parathyroid hormone (PTH) concentration, or abnormal GFR, or a combination thereof.

The method of the invention treats a subject having one or more signs of stage 1 CKD to prevent expression of CKD in the subject, or to treat a subject having stage 1 CKD to prevent disease progression to stage 2 CKD. And the like, and to prevent the progression of nephropathy.

6.4. calcification( calcification Prevention method

Subjects with signs of CKD can treat calcification of soft tissues associated with CKD by administering to the subject a therapeutically effective amount of the stabilized lanthanum carbonate formulation of the present invention.

Calcification can occur in any soft tissue. Soft tissue may include arterial tissue, heart muscle, heart valves, joints, skin and breast tissue.

6.5. How to treat secondary hyperthyroidism

A subject suffering from or having one or more signs of secondary hyperthyroidism may be treated by administering to the subject a therapeutically effective amount of a stabilized lanthanum carbonate formulation of the invention.

Parathyroidism is defined as a disease in subjects with raw PTH levels of about 150 pg / mL or higher. Signs of hyperparathyroidism include hypocalcemia (ie, blood calcium levels below about 8.5 mg / dL), hyperphosphatemia (ie, blood phosphate levels above about 4.5 mg / dL), and bone related diseases (eg, Fractures or bone pain).

7. Stabilized Lanthanum Carbonate Formulation  administration

Lanthanum carbonate formulations may be administered orally to a subject according to the invention in various dosage forms, from about 125 to about 2000 mg of lanthanum carbonate as the lanthanum element per meal. Dosage for a typical adult can be 375 mg to 6000 mg per day. More preferably, the dosage is 375 to 3750 mg / 1 day. This dosage may be divided in each meal and may be, for example, 250, 500, 750, or 1000 mg tablets three times a day. Serum plasma levels can be observed weekly, and dosages can be modified until reaching optimal plasma phosphate levels. Administration can be effected with an uninterrupted regime, which can be a permanent regimen for the treatment of long term regimes, eg chronic diseases.

Lanthanum carbonate formulations may be administered orally, for example in the form of tablets, capsules, chewable formulations, and the like. Usually, due to kidney dysfunction, subjects with hyperphosphatemia need to limit their liquid intake. Therefore, lanthanum carbonate formulations that can take no liquid or only small amounts are preferred. For example, lanthanum carbonate formulations can be sprinkled on food in the form of beads, chewable or crushed tablets, powders, or sieved granules.

Lanthanum carbonate formulations are formulated to maintain a low level of lanthanum at the plasma level, for example, for a dose of 3 g per day (e.g., 1 g three times a day), at least for each of C _max , T _max , And AUC is preferably maintained as low as provided by an average concentration curve of less than 1.5 ng / ml, about 12 hours, and 50 ng.hr/ml. Preferably, C _max and AUC are less than 1.1 ng / ml and less than 32 ng.hr/ml, more preferably C _max and AUC are less than 0.5 ng / ml and 20 ng.hr/ml for each dose. to be. T _max The value is essentially unaffected by the dose, and the C _max and AUC values increase proportionally with the dose relative to the oral dose up to about 1500 mg / 1 day. C _max and AUC values are constant for doses for doses of about 1500 mg / day or more. All of the above parameters have the same meanings as commonly used.

It will be appreciated that the amount of each component incorporated into the formulation and the duration of treatment in accordance with the present invention may vary depending on the requirements of the treatment of each subject. The exact dosage regimen will be determined by the physician or veterinarian, taking into account such factors as weight, age and specific symptoms. The physician or veterinarian may titrate the dose of lanthanum compound administered to the subject to determine the exact dosage required for treatment. For example, a doctor can measure a patient's blood phosphate levels, set a specific lanthanum dosage for a patient required for one week, and assess a patient's phosphate level after one week to determine if the dosage is adequate. There will be.

For the purposes of the examples, the term "hydrated lanthanum carbonate" refers to lanthanum carbonate having a water content of approximately 4-5 moles of water.

1. Stabilized hydrated lanthanum, a chewable tablet Carbonate  Manufacturing (250 mg , 500 mg, 750 mg , And 1000 mg )

The method of preparation involves filtering and blending the active ingredient and additives into a sieve and then directly compressing them. More specifically, the steps are as follows:

a) blending lanthanum carbonate and additives such as dexrate, colloidal silicon dioxide, talc (optional component) and magnesium stearate.

b) Compress the formulation using standard instruments up to the target compression weight.

In the following table, the general content described above is described.

2. Example  2: sorbitol Stabilizer  Stabilized lanthanum containing Carbonate  Chewable tablets Formulation

The following lanthanum carbonate chewable tablet formulation comprising sorbitol was prepared as described in Example 1.

Formulation Ingredient Wt% in tablets Hydrated Lanthanum Carbonate 63.6% Glyceryl Dibehenate 3.0% Colloidal silicon dioxide (e.g. Aerosil ^® 200) 2.0% Sorbitol 30.4% Talc 1.0%

3. Example  3: Mannitol Stabilizer  Stabilized lanthanum containing Carbonate  Chewable tablets Formulation

The following lanthanum carbonate chewable tablet formulations comprising mannitol were prepared as described in Example 1.

Formulation Ingredient Wt% in tablets Hydrated Lanthanum Carbonate 63.6% Glyceryl Dibehenate 3.0% Colloidal silicon dioxide (e.g. Aerosil ^® 200) 2.0% Mannitol 30.4% Talc 1.0%

4. Example  4: Xylitol Stabilizer  Stabilized lanthanum containing Carbonate  Chewable tablets Formulation

The following lanthanum carbonate chewable tablet formulations comprising xylitol were prepared as described in Example 1.

Formulation Ingredient Wt% in tablets Hydrated Lanthanum Carbonate 63.6% Glyceryl Dibehenate 3.0% Colloidal silicon dioxide (e.g. Aerosil ^® 200) 2.0% Xylitol 30.4% Talc 1.0%

5. Example  5: monosaccharides and disaccharides Stabilizer  Using lanthanum Carbonate Formulation  Stabilization

To determine what class of saccharide additives can slow or prevent the appearance of decarboxylation products in thermally stressed solid lanthanum carbonate mixtures and moisture stressed solid lanthanum carbonate mixtures, approximately 4-5 moles of water. An additive compatibility study of hydrated lanthanum carbonate and anhydrous lanthanum carbonate having a corresponding moisture content was carried out.

Conditions were used that would result in the formation of the decarboxylation product in substantially pure hydrated lanthanum carbonate within one week. Hydrated lanthanum carbonate and test additives were prepared at 1: 1 or 96: 4 (weight) or anhydrous lanthanum carbonate and test additives were prepared at 1: 1 (weight) and stressed, and samples were subjected to XRPD (x-ray powder diffraction).

5.1. Substances and Methods

5.1.1. Sample and Reagent

Substantially pure hydrated lanthanum carbonate and anhydrous lanthanum carbonate samples were used for this study. Test additives (D-mannitol, D-sorbitol, dexrate, β-cyclodextrin, corn syrup, anhydrous lactose, lactose monohydrate, and microcrystalline cellulose) were purchased from the supplier and used as is.

5.1.2. Mixture manufacturing

The weighed sample, consisting of hydrated lanthanum carbonate / additive (1: 1 or 96: 4 weight) or anhydrous lanthanum carbonate / additive (1: 1 weight), is sealed in a scintillation vial and the Turbula mixer Placed on top. The samples were mixed for 10 minutes, allowing the samples to mix evenly.

5.1.3. Humidity chamber  Produce

A saturated salt solution of Na ₂ SO ₄ 10H ₂ O (up to 95% relative humidity) or NaNO ₃ (65% RH) was prepared and placed in a sealed chamber. The chamber was kept at 60 ° C. overnight and the presence of solids was checked after 24 hours. These chambers were later used for stress studies of various additive / lanthanum carbonate mixtures. Lower humidity conditions were used for the D-sorbitol and dextrate additives because they melt under more extreme conditions of 60 ° C./95% RH.

5.1.4. x-ray powder diffractometer XRPD )

XRPD analysis was performed using a Shimadzu XRD-6000 x-ray powder diffractometer using Cu Kα radiation. The sample was placed in an aluminum holder with a silicone insert to prepare the sample for analysis.

5.2. Results and review

5.2.1. Characterization of Test Substance

Unstressed, substantially pure hydrated lanthanum carbonate was crystallized by XRPD (FIG. 1). Characterized by XRPD for the purpose of specificity analysis of the additives and anhydrous lanthanum carbonate used in this study, their patterns are shown in FIG. 2. All the additives showed sufficient specificity, ie allowing the observation of lanthanum hydroxycarbonate (HC) formation.

5.2.2. Hydrated Lanthanum Carbonate  Stress study

At the beginning of the experiment, to establish a baseline for monitoring decarboxylation, hydrated lanthanum carbonate was stressed under two conditions: 60 ° C./95% RH and 60 ° C./65% RH. Each sample was withdrawn after 1,2,3,4, and 7 days and immediately analyzed by XRPD. In addition, pulls were made on days 14 and 21 under 60 ° C./65% RH conditions.

3 (60 ° C./95% RH conditions) and FIG. 4 (60 ° C./65% RH conditions) summarize the experimental results. Under 60 ° C./95% RH conditions, the decarboxylation product HC is initially found after 1 day. When hydrated lanthanum carbonate was under 60 ° C./65% RH stress conditions, HC was first discovered after one day (FIG. 4).

5.2.3. Hydrated Lanthanum Carbonate / D- Mannitol  Stress study (60 degrees Celsius / 65% RH  Condition)

A 1: 1 mixture (weight) of hydrated lanthanum carbonate / D-mannitol was stressed and analyzed over a period of 2 weeks. The results are shown in FIG. No decarboxylation was observed in the hydrated lanthanum carbonate during the experimental period.

5.2.4. Hydrated Lanthanum Carbonate Stress study (60 degrees Celsius / 65% of / D-sorbitol RH  Condition)

The 1: 1 mixture (weight) of hydrated lanthanum carbonate / D-sorbitol was stressed and analyzed over a period of 3 weeks. The results are shown in FIG. No decarboxylation was observed in the hydrated lanthanum carbonate during the experimental period.

5.2.5. Hydrated Lanthanum Carbonate Of Dexrate  Stress study (60 degrees Celsius / 65% RH  Condition)

The 1: 1 mixture (weight) of hydrated lanthanum carbonate / dextrin was stressed and analyzed over a period of 3 weeks. The results are shown in FIG. No decarboxylation was observed in the hydrated lanthanum carbonate during the experimental period.

5.2.6. Hydrated Lanthanum Carbonate / β- Cyclodextrin  Stress study (60 degrees Celsius / 95% RH  Condition)

The 1: 1 mixture (weight) of hydrated lanthanum carbonate / β-cyclodextrin was stressed and analyzed over a period of 2 weeks. The results are shown in FIG. The presence of decarboxylation of the product HC was first detected 1 day after the stress treatment.

5.2.7. Hydrated Lanthanum Carbonate / Corn starch stress study (60 degrees Celsius / 95% RH  Condition)

A 1: 1 mixture (weight) of hydrated lanthanum carbonate / cornstarch was stressed and analyzed over a period of 2 weeks. The results are shown in FIG. The presence of decarboxylation of the product HC was first detected 1 day after the stress treatment.

5.2.8. Lanthanum anhydride Carbonate / D- Mannitol  Stress study (60 degrees Celsius / 95% RH  Condition)

The 1: 1 mixture (weight) of anhydrous lanthanum carbonate / D-mannitol was stressed and analyzed over a period of 2 weeks. The results are shown in FIG. Decarboxylation of anhydrous lanthanum carbonate was not observed over the course of the experiment.

5.2.9. Hydrated Lanthanum Carbonate Anhydrous Lactose And Hydrated Lanthanum Carbonate Lactose Monohydrate  Stress study (60 degrees Celsius / 95% RH  Condition)

A 1: 1 mixture (weight) of hydrated lanthanum carbonate / anhydrous lactose and hydrated lanthanum carbonate / lactose monohydrate was stressed and analyzed over a period of 2 weeks. The respective results for hydrated lanthanum carbonate / anhydrous lactose and hydrate lanthanum carbonate / lactose monohydrate are summarized in FIGS. 11 and 12. Detectable decarboxylation of hydrated lanthanum carbonate was not observed in any mixtures during the course of the experiment.

5.2.10. Hydrated Lanthanum Carbonate Microcrystalline Cellulose  Stress study (60 degrees Celsius / 95% RH  Condition)

The 1: 1 mixture (weight) of hydrated lanthanum carbonate / microcrystalline cellulose showed evidence of decarboxylation of hydrated lanthanum carbonate 1 day after stress at 60 ° C. and 95% relative humidity. The results are summarized in FIG.

5.2.11. 96: 4 (weight) hydrated lanthanum Carbonate / D- Mannitol  Hydrated lanthanum in the mixture Carbonate  stabilize

A 96: 4 (weight) hydrated lanthanum carbonate / D-mannitol mixture study was performed using the method described above. The mixture was stressed for 14 days at 60 ° C. and 95% relative humidity. The results are summarized in FIG.

After 7 days of stress, no decarboxylation of hydrated lanthanum carbonate in the mixture was detected. After 14 days of stress, only traces of decarboxylation of hydrated lanthanum carbonate in the mixture were detected.

5.3. conclusion

The above results indicate that monosaccharides and disaccharides, such as mannitol, sorbitol, lactose and dexrate, reduce or eliminate decarboxylation to lanthanum hydroxycarbonate in formulations containing lanthanum carbonate (anhydrous and hydrated forms). To provide stabilization protection in Polysaccharides such as cornstarch, beta-cyclodextrin and microcrystalline cellulose do not provide this protection, and thus talc in formulations containing polysaccharides at a similar rate to unformulated drug substance exposed under the same conditions. Compounding was observed.

6. Example  6: lanthanum hydrated under atmospheric conditions Carbonate Decarboxylation  speed

Unformulated hydrated lanthanum carbonate and formulated hydrated lanthanum carbonate tablets containing approximately 50% (weight) dexrate were subjected to 25 ° C./60% RH, 30 ° C./60% RH, and 40 ° C. / Exposed under standard ICH stability conditions of 75% RH. Samples were taken out after this time and tested for lanthanum hydroxycarbonate content using x-ray powder diffraction.

FIG. 15 demonstrates the decarboxylation rate of unformulated hydrated lanthanum carbonate at standard ICH stability conditions of 25 ° C./60% RH, 30 ° C./60% RH, and 40 ° C./75% RH. Demonstrates significant degradation of hydrated lanthanum carbonate. Degradation results at 25 ° C./60% RH conditions suggest the need to store unformulated drug substance under refrigerated conditions to slow down the rate of degradation. In contrast, decarboxylation may not be detected in similarly stored tablets formulated with about 50% (weight) dexrate, as provided in FIG. 15.

This experiment demonstrated that dexrate stabilizes hydrated lanthanum carbonate by preventing decarboxylation at standard atmospheric conditions.

The present invention should not be limited to the specific embodiments described herein. Indeed, from the foregoing detailed description, those skilled in the art will recognize that various modifications of the invention are possible in addition to those described above. Such modifications are also intended to fall within the scope of the appended claims.

All references cited herein, ie all patent documents, published patent applications and published scientific papers and books, are all incorporated herein by reference.

Claims (24)

As stabilized lanthanum carbonate composition comprising a pharmaceutically effective amount of lanthanum carbonate having the general formula and at least one pharmaceutically acceptable monosaccharide or disaccharide stabilizer: _{La 2 (CO 3) 3 ·} xH 2 O Wherein x is a number from 0 to 10 and the monosaccharide or disaccharide is present in an amount of at least about 1 wt% based on the total weight of the composition. The composition of claim 1, wherein the monosaccharide or disaccharide is present in an amount from about 1 to about 90 wt% based on the total weight of the composition. The composition of claim 1, wherein the monosaccharide or disaccharide is sucrose, glucose, galactose, fructose, dextrose, ribose, maltose, sorbitol, xylitol, mannitol, lactose, dextrate, or a mixture thereof. . The composition of claim 3, wherein the monosaccharide or disaccharide is dextrate present in an amount of about 40 to about 80 wt%, based on the total weight of the composition. The composition of claim 3, wherein the monosaccharide or disaccharide is sorbitol present in an amount of about 20 to about 80 wt%, based on the total weight of the composition. The composition of claim 3, wherein the composition further comprises a lubricant. The composition of claim 6 wherein the lubricant is magnesium stearate, talc, polyethylene glycol, silica, colloidal anhydrous silica, colloidal silicon dioxide, hydrogenated vegetable oil, glyceryl behenate or glyceryl monostearate. 7. The composition of claim 6, wherein the composition further comprises a glidant. The composition of claim 8 wherein the glidant is silica, colloidal anhydrous silica, colloidal silicon dioxide, or talc. 10. The composition of claim 9, wherein the composition comprises the following components and the lanthanum carbonate below is hydrated with a water content equivalent to approximately 4-5 moles of water: ingredient wt% Lanthanum carbonate 26.5 Dexrate 69.3 Colloidal silicon dioxide 2 Talc 1.7 Magnesium stearate 0.5 10. The composition of claim 9, wherein the composition comprises the following components and the lanthanum carbonate below is hydrated with a water content equivalent to approximately 4-5 moles of water: ingredient wt% Lanthanum carbonate 63.6 Colloidal silicon dioxide 2 Talc One Sorbitol 30.4 Glyceryl Dibehenate 3.0 10. The composition of claim 9, wherein the composition comprises the following components and the lanthanum carbonate below is hydrated with a water content equivalent to approximately 4-5 moles of water: ingredient wt% Lanthanum carbonate 45.8 Dexrate 51.1 Colloidal silicon dioxide 2.1 Magnesium stearate 1.0 A method of treating hyperphosphatemia comprising administering a pharmaceutically effective amount of lanthanum carbonate having the general formula and a therapeutically effective amount of a stabilized lanthanum carbonate composition comprising at least one pharmaceutically acceptable monosaccharide or disaccharide stabilizer : _{La 2 (CO 3) 3 ·} xH 2 O Wherein x is a number from 0 to 10 and wherein said monosaccharide or disaccharide is present in an amount of at least about 1 wt% based on the total weight of the composition. The method of claim 13, wherein the monosaccharide or disaccharide is present in an amount from 1 to 90 wt% based on the total weight of the composition. The method according to claim 13, wherein the monosaccharide or disaccharide is monosaccharide or disaccharide is sucrose, glucose, galactose, fructose, dextrose, ribose, maltose, sorbitol, xylitol, mannitol, lactose, dextrate, or mixtures thereof. Characterized in that the method. The method of claim 15, wherein the monosaccharide or disaccharide is dextrate present in an amount from about 20 to about 80 wt%, based on the total weight of the stabilized composition. The method of claim 15, wherein the monosaccharide or disaccharide is sorbitol present in an amount of about 20 to about 80 wt% based on the total weight of the stabilized composition. The method of claim 15, wherein the stabilized composition further comprises a lubricant. 19. The method of claim 18, wherein the lubricant is magnesium stearate, talc, polyethylene glycol, silica, colloidal anhydrous silica, colloidal silicon dioxide, hydrogenated vegetable oil, glyceryl behenate or glyceryl monostearate. The method of claim 19, wherein the stabilized composition further comprises a glidant. 21. The method of claim 20, wherein the glidant is silica, colloidal anhydrous silica, colloidal silicon dioxide, or talc. The method of claim 21, wherein the stabilized composition comprises the following components and the lanthanum carbonate below is hydrated with a water content equivalent to approximately 4-5 moles of water: ingredient wt% Lanthanum carbonate 26.5 Dexrate 69.3 Colloidal silicon dioxide 2 Talc 1.7 Magnesium stearate 0.5 The stabilized composition of claim 21 comprising the following components, wherein the lanthanum carbonate below is hydrated with a water content equivalent to approximately 4-5 moles of water: ingredient wt% Lanthanum carbonate 63.6 Colloidal silicon dioxide 2 Talc One Sorbitol 30.4 Glyceryl Dibehenate 3.0 The stabilized composition of claim 21 comprising the following components, wherein the lanthanum carbonate below is hydrated with a water content equivalent to approximately 4-5 moles of water: ingredient wt% Lanthanum carbonate 45.8 Dexrate 51.1 Colloidal silicon dioxide 2.1 Magnesium stearate 1.0

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